GDF-15 Is Necessary In Preserving MSC-mediated Right Ventricle Function In Porcine Pressure-overload Model: Implications For The MSC Clinical Trial In HLHS
David Morales, Gregory Bittle, MD, Rachana Mishra, PhD, Nicholas Pietris, MD, Nathaniel Parchment, Gregory Boyajian, Sudhish Sharma, PhD, Progyaparamita Saha, PhD, Muthukumar Gunasekaran, PhD, Deqiang Li, PhD, Sunjay Kaushal, MD, PhD.
University of Maryland, Baltimore, MD, USA.
Objective: Previously, we have shown that Intramyocardial injection of mesenchymal stem cells (MSCs) preserves right ventricle (RV) function and decreases hypertrophy through possible activation of GDF-15 anti-hypertrophy pathway in a porcine model of pressure overload. We aimed to investigate the role of GDF-15 in MSC regenerative therapy.
Methods: MSCs were treated with a GDF-15 shRNA plasmid (GDF-15 KD). In 7-10 kg Yorkshire swine, we banded the pulmonary artery to create pressure-overload in the RV and injected into the RV free wall either saline (control), MSCs or GDF-15 KD MSCs. GDF-15 is secreted in the exosome of MSCs so MSCs were treated with GW4869 to stop exosome production and injected into RV free wall post banding as well.
Results: The control and GDF-15 KD groups demonstrated decreased FAC (fractional area change) on POD 28 compared to baseline (49.3% to 37.3% for controls and 52.8% to 34.2%). The MSC group demonstrated preserved FAC at 28 days (51.8% to 55%). GW4869 MSC treatment demonstrated reduced FAC from baseline at POD 28 (54.5% to35.1%).
Conclusion: This current data demonstrates GDF-15 is secreted in the exosome, and its removal nullifies any therapeutic effect of MSCs. Therefore, GDF-15 plays a critical role in RV functional preservation in pressure overload possibly by controlling maladaptive hypertrophy which has direct implications to our MSC HLHS clinical trial.